TRIM Proteins Polarize DNA Sensing Outcomes During the Innate Immune Response to Mycobacterium Tuberculosis Grant uri icon


  • Project SummaryMycobacterium tuberculosis (Mtb) is an incredibly successful human pathogen that currently infects one-thirdof the world''s population and kills 1.5 million people every year. While interaction of Mtb bacilli andmacrophages activates numerous antimicrobial pathways, this bacterium has evolved an exquisite array ofadaptations to counteract such responses in order to establish a niche and promote infection. As such, whenMtb is internalized into macrophages, innate immune sensing of bacterial DNA in the host cell cytosol triggersboth anti-bacterial and pro-bacterial responses: selective autophagy destroys a population of bacilli andrestricts Mtb growth, while activation of the antiviral type I interferon response promotes bacterial infection andpathogenesis. An innate immune kinase called TBK1 is central to both of these processes; however, themechanism by which this kinase comprises both selective autophagy and type I interferon signaling complexesis unknown. Our new work has uncovered an important role for the tripartite motif protein TRIM14 in regulatingthe kinase TBK1 and eliciting the type I IFN response during Mtb infection. We hypothesize that TRIM14 is akey modulator of DNA sensing during Mtb infection and that post-translational modification of TRIM14influences the shuttling of TBK1 away from selective autophagy to promote type I IFN production. Usingbiochemical, proteomic and microscopy-based approaches we will (1) determine the mechanism by whichTRIM14 influences DNA sensing outcomes during Mtb infection (2) elucidate the role of post-translationalmodifications in regulating TRIM14 and (3) determine the role of TRIM30α in negatively regulating type I IFNproduction and controlling Mtb pathogenesis. Because these two DNA sensing pathways lead to such strikinglydifferent disease outcomes, there is an obvious opportunity to develop therapeutics that target molecules likeTRIMs, in hopes of activating selective autophagy while inhibiting the type I interferon response during Mtbinfection.

date/time interval

  • 2016 - 2020